Influenza (flu) kills over 30 million people in the US yearly and a new flu pandemic caused by a new heterosubtypic virus could kill many millions. Current vaccines use inactivated virus that induce low levels of Ab that react with the outer coat proteins of flu that undergo rapid shift and drift, leaving us vulnerable to new strains. T cells recognize internal core proteins that change much less so it is extremely important to determine to what extent T cell immunity can mediate protection to flu, to evaluate if vaccines that prime T cells are likely to be valuable. Our recent studies show in a definitive model that primed CD4 T cells provide robust protection by enhancing B production and by unexpected cytotoxic mechanisms, independently of IFNy production. Here we will exploit an adoptive transfer model that will allow us to isolate mechanisms in primed subsets of CD4 donor T cells and then transfer those donor cells to unprimed recipients. This will allow us evaluate how each mechanism acts in promoting protection and how they may synergize with one another. We have shown that naTve CD4 T cells lacking perform, develop helper but not cytolytic activities, while those lacking SAP (an intracellular signaling molecule associated with SLAM) develop primed cells with the reciprocal pattern. These tools further delineate these two mechanisms determining how well each works, what their targets are and how they synergize. We will also compare these two activities in the protection given by effectors on one hand and resting memory CD4 cells on the other. Moreover we will determine CDS T cells, known for their cytolytic activities are redundant when CD4 T cells are cytolytic or if they synergize with CD4 T cells in providing protection. We suggest that the studies will yield new insights into the full potential of CD4 T cell priming to contribute to protection against emerging heterosubtypic strains of flu and that they will unambiguously identify correlates of protection for CD4 immunity to flu. These findings may provide basic support for the future development of new vaccine strategies based on inducing T cell immunity that could augment current approaches and provide much better protection in the event of flu pandemic.